Almost all HIV infected persons are infected with herpes simplex viruses (HSV). From 40-95% of HIV positive persons are HSV-2 seropositive. Within the last funding period our studies have indicated that among men who have sex with men, prior HSV-2 infection, infection significantly increases the likelihood of acquiring HIV-1 (R.R. 1.7, P=.04). Conversely, among HIV and HSV-2 co-infected persons, high titers of HIV-1 RNA are found in almost all genital lesions for a prolonged duration, suggesting HSV-2 may play an important role in increasing the efficiency of transmission of HIV-1. In addition, frequent subclinical HSV-2 reactivation may be a significant co- factor in initiating bursts of HIV-1 replication in genitourinary compartments and the total HIV-1 viral load. Our proposed studies are centered upon answering these issues. They include: 1) Collaborating with NIAID supported HIVNET to evaluate whether prior HSV-2 infection increases the risk of HIV-1 acquisition in women; 2) Conducting a series of studies to evaluate in subclinical HSV shedding causes HIV-1 replication in semen, cervicovaginal and rectal mucosa; 3) evaluating if antiviral therapy for HSV can suppress HIV replication in genital lesions; 4) Determining if chronic daily acyclovir therapy reduces plasma virus load. HSV infection also affords a unique opportunity for evaluating whether highly active anti-retroviral therapy (HAART) effectively influences host immune control of an opportunistic pathogen. Proposed studies evaluate the frequency of HSV reactivation by quantitative PCR prior to, 4 months after, and 12 months after initiation of HAART in HIV+ persons with high and lower CD4 T cell counts. The above studies will define what management strategies can reduce the morbidity of HSV infection on HIV progression. They will also provide important information on the potential role HSV has in the spread of sexually transmitted and sexually acquired HIV and define potential intervention strategies for interrupting such transmission.